Disease | Orofaciodigital syndrome |
|---|
Inheritance | Autosomal recessive |
Prevalence | <1 / 1 000 000 Source: ORPHA:2919 |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | CLINGEN - NONE. GENCC - Strong (Invitae). BabySeq - none. HGMD curation below. |
Clinical Validity Scoring Notes and points | PMID: 34008892 NM_001031725.6:c.[751T>C]; [1597-6T>G], p.(Ser251Pro) variants in supplement table 2, found via WES, in trans, but they only give a MIM phenotype. In case 8006. No specific phenotype info. Not scoring either variant.
PMID: 28289185 Homozygous c.754G>A p.Gly252Arg (absent gnomAD) in case 1. Per table S1, this is a patient w/ cleft lip, abnormal frenuale, lobulated tongue, Post-axial polydactyly, LSE: low-set ears, PrP: Pre-axial polydactyly, syndactyly. 0.5x0.5 points = 1 POINT.
PMID: 38693247 In supplement, compound het variants NM_001031725:exon3:c.G953A:p .R318H; exon2:c.26delT:p.I9Tfs*16 . No specific phenotype given, this is a cerebral palsy cohort. No evidence awarded for the OFD syndrome
PMID: 23972372 c.1100T>G; NP_001026895.2: p.V367G, absent gnomAD, 2 large consanguineous Arab families with OFD syndrome. They state that the “variants survived the test of segregation” but it isn’t very clear which individuals had testing done on. I’m going to assume that the affected individuals were tested, but could consider downgrading segregations here. Family 1 with c.1100T>G; NP_001026895.2: p.V367G, absent gnomAD. 3 affected individuals total, 2 affected segregations. 0.5x2 = 1 POINT VARIANT, 2 SEGS Family 2 had c.1600G>A p.Gly534Arg. In gnomAD but very low, only 3 alleles. 4 affected individuals and 3 AR segregations. 0.5x2 = 1 POINT VARIANT, 3 SEGS Ddx59 expressed in developing palate and limb buds of mouse embryos. EXPRESSION - 1 POINT Immunoblot analysis of patient fibroblasts revealed marked reduction in protein abundance compared to controls
PMID: 32552793 and 37644014- author overlap with 23972372, homozygous in table S3 in 32552793 and table S1 in 37644014, assuming it is the same patient. No points awarded. PMID: 38160027 c.1450A>G p.R484G, only 2 alleles in gnomAD v4. Phenotype is a little different in this proband, with microcephaly, tongue hamartoma. Variant found via WES. 0.5x2 = 1 point
PMID: 28711741 PMID: 29127725 c.185delT p.(Phe62Serfs*14) -7/1180048 European non-Finnish chr in gAD v4. homozygous in a family with OFD syndrome, including microcephaly, ID, DD, epilepsy. Variant segregated in an affected sib. 2x1 = 4 POINT, 1 AR SEG A Drosophila model using a homolog of DDX59 had shortened lifespan and abnormalities in neuronal structures (fig 2.). Since this is a homolog, I’m reducing points for animal model to 1 POINT
SEGREGATION EVIDENCE - 6 SEGS, 2 POINTS Source: |
Clinical Validity Points Total | 14 Source: |
Clinical Validity Classification | Expand |
|---|
| title | Classifications (pts) |
|---|
| Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed |
| DEFINITIVE Source: 28289185, 23972372, 38160027, 28711741, 29127725, |
Molecular Mechanism | Expand |
|---|
| Loss of function Gain of function Dominant negative Unknown Other |
| Suspected Loss of function (not enough evidence yet) Variants/LOF evidence: |
Penetrance | Expand |
|---|
| Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) |
(list source/PMID) | Source: |
Age of Onset | Expand |
|---|
| Congenital Pediatric Adolescent Adulthood Late adulthood |
(list source/PMID) | |
Severity | Expand |
|---|
| Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. |
| |
Clinical Features | Postaxial polydactyly microcephaly, intellectualdisability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events (PMID: 29127725) Sources: |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary | Expand |
|---|
| - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited |
| The DDX59 gene is associated with autosomal recessive orofaciodigital syndrome. Clinical features include cleft palate/uvula, lobulated tongue, frontal bossing, hypertelorism, postaxial polydactyly, and impaired intellectual development (PMID 28711741). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 01/14/25 CASE: 2106077007 SM-MPQ1T D-091113270-BH-4161-P-A |